Summary of Work: Evidence indicates that lipid metabolites may play a role in breast cancer. Some data support a role for linoleic acid metabolism while other more recent data indicate the over-expression of PGHS-2 in human breast tumor. No expression of PGHS-2 was observed in normal human breast tissue. The EGFR and the oncogenes erb-2 play an important role in breast cancer. Since SHE cells represent a model system for studying the interaction of lipids with the EGFR signaling pathway we examined how the presence of erb-2 would alter lipid metabolism. We transfected normal SHE fibroblasts with plasmid DNA vectors containing the retroviralv-erbB oncogene or its cellular homolog c-erbB-2 and established stable transfected cell lines. erbB-Transfected cells demonstrate increased lipoxygenase metabolism of both linoleic and arachidonic acid. We have examined the metabolism of linoleic and arachidonic acid in a variety of human breast carcinoma cell lines which vary in their expression of EGF receptor, c-erbB-2/HER2, and estrogen receptor. We have observed a close association between high levels of c-erbB-2 and EGF receptor expression and the extent of linoleic acid metabolism in these cells. Inhibition of lipoxygenase metabolism attenuates DNA synthesis in the erbB-2/EGFR overexpressing cells. We are currently examining the EGFR signaling pathway in human breast cells and how lipids metabolites can alter EGFR- dependent phosphorylation events.